title: Prototypical Recombinant Multi-Protease-Inhibitor-Resistant Infectious Molecular Clones of Human Immunodeficiency Virus Type 1.
abstract: The many genetic manifestations of HIV-1 protease inhibitor (PI) resistance present challenges to research into the mechanisms of PI resistance and the assessment of new PIs. To address these challenges, we created a panel of recombinant multi-PI-resistant infectious molecular clones designed to represent the spectrum of clinically relevant multi-PI-resistant viruses. To assess the representativeness of this panel, we examined the sequences of the panel's viruses in the context of a correlation network of PI resistance amino acid substitutions in sequences from more than 10,000 patients. The panel of recombinant infectious molecular clones comprised 29 of 41 study-defined PI resistance amino acid substitutions and 23 of the 27 tightest amino acid substitution clusters. Based on their phenotypic properties, the clones were classified into four groups with increasing cross-resistance to the PIs most commonly used for salvage therapy: lopinavir (LPV), tipranavir (TPV), and darunavir (DRV). The panel of recombinant infectious molecular clones has been made available without restriction through the NIH AIDS Research and Reference Reagent Program. The public availability of the panel makes it possible to compare the inhibitory activities of different PIs with one another. The diversity of the panel and the high-level PI resistance of its clones suggest that investigational PIs active against the clones in this panel will retain antiviral activity against most if not all clinically relevant PI-resistant viruses.
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Stanford University, Stanford, California, USA.
authors.forename: Vici
authors.initials: V
authors.lastname: Varghese
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Stanford University, Stanford, California, USA.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Mitsuya
authors.affiliation: Kaiser-Permanente Medical Care Program-Northern California, San Francisco, California, USA.
authors.forename: W Jeffrey
authors.initials: WJ
authors.lastname: Fessel
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Stanford University, Stanford, California, USA.
authors.forename: Tommy F
authors.initials: TF
authors.lastname: Liu
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Stanford University, Stanford, California, USA.
authors.forename: George L
authors.initials: GL
authors.lastname: Melikian
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Stanford University, Stanford, California, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Katzenstein
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, University of Massachusetts, Worcester, Massachusetts, USA.
authors.forename: Celia A
authors.initials: CA
authors.lastname: Schiffer
authors.affiliation: Department of Statistics, Stanford University, Stanford, California, USA.
authors.forename: Susan P
authors.initials: SP
authors.lastname: Holmes
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Stanford University, Stanford, California, USA rshafer@stanford.edu.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Shafer